Zhenlin Yan

Prognostic Nomogram for Intrahepatic Cholangiocarcinoma After Partial Hepatectomy

PURPOSE This study aimed to establish an effective prognostic nomogram for intrahepatic cholangiocarcinoma (ICC) after partial hepatectomy. PATIENTS AND METHODS The nomogram was based on a retrospectively study on 367 patients who underwent partial hepatectomy for ICC at the Eastern Hepatobiliary Surgery Hospital from 2002 to 2007. The predictive accuracy and discriminative ability of the nomogram were determined by concordance index (C-index) and calibration curve and compared with five currently used staging systems on ICC. The results were validated using bootstrap resampling and a prospective study on 82 patients operated on from 2007 to 2008 at the same institution. RESULTS On multivariate analysis of the primary cohort, independent factors for survival were serum carcinoembryonic antigen, CA 19-9, tumor diameter and number, vascular invasion, lymph node metastasis, direct invasion, and local extrahepatic metastasis, which were all selected into the nomogram. The calibration curve for probability of survival showed good agreement between prediction by nomogram and actual observation. The C-index of the nomogram for predicting survival was 0.74 (95% CI, 0.71 to 0.77), which was statistically higher than the C-index values of the following systems: American Joint Committee on Cancer (AJCC) seventh edition (0.65), AJCC sixth edition (0.65), Nathan (0.64), Liver Cancer Study Group of Japan (0.64), and Okabayashi (0.67; P < .001 for all). It was also higher (0.74) in predicting survival for the mass-forming type of ICC (P < .001). In the validation cohort, the nomogram discrimination was superior to the five other staging systems (C-index: 0.75 v 0.60 to 0.63; P < .001 for all). CONCLUSION The proposed nomogram resulted in more-accurate prognostic prediction for patients with ICC after partial hepatectomy.

Overexpression of aspartyl-(asparaginyl)-β-hydroxylase in hepatocellular carcinoma is associated with worse surgical outcome†

The association between the overexpression of aspartyl‐(asparaginyl)‐β‐hydroxylase (AAH) and the invasiveness of hepatocellular carcinoma (HCC) in vitro has been reported. However, the prognostic value of AAH expression in HCC remains unclear. The purpose of this study was to investigate the relationship between AAH expression, tumor recurrence, and patient survival. We identified AAH as the most overexpressed gene in HCC by way of complementary DNA microarray hybridization. A prospective study of 233 patients undergoing curative resection indicated that AAH expression was an independent factor affecting recurrence (hazard ratio [HR] 3.161, 95% confidence interval [CI] 2.115‐4.724, P < 0.001) and survival (HR 2.712, 95% CI 1.734‐4.241, P < 0.001). Patients with AAH overexpression had a poorer prognosis than those with AAH underexpression (P < 0.001 for both recurrence and survival). In Barcelona Clinic Liver Cancer stage A patients with AAH overexpression or underexpression, the tumor recurrence and survival rates were also statistically different (45% and 85% versus16% and 33% in 1‐ and 3‐year cumulative recurrence rates, respectively; 73% and 37% versus 90% and 80% in 1‐ and 3‐year survival rates, respectively; P < 0.001 for both). Furthermore, in stage A patients with tumors measuring ≤5 cm in diameter, the time to recurrence was 26.7 ± 1.6 versus 51.9 ± 2.8 months, and the 1‐ and 3‐ year survival rates were 97% and 52% versus 100% and 90% in AAH overexpression and underexpression patients, respectively (P < 0.001 for both). Conclusion: AAH overexpression in HCC is strongly correlated with worse surgical outcome, and this molecule likely provides a more precise prognostic predictor in early stage HCCs. HEPATOLOGY 2010

Background Progenitor Activation Is Associated With Recurrence After Hepatectomy of Combined Hepatocellular-Cholangiocarcinoma

Hepatic progenitor cells (HPC) play important roles in both liver regeneration and carcinogenesis. Combined hepatocellular‐cholangiocarcinoma (CHC), a malignant primary liver tumor with poor prognosis, is thought to be of HPC origin. However, the prognostic significance of this etiology is not well defined. Therefore, we retrospectively investigated the relationship of HPC‐related pathological features and long‐term outcome in patients with CHC in our department. In a cohort of 80 patients identified between 1997 and 2003, including 70 patients who underwent resection with curative intent, overall survival (OS) and disease‐free survival (DFS) were correlated with the proliferative activity of nontumor ductular reaction (DR) and the expression levels of HPC and biliary markers including α‐fetoprotein (AFP), keratin 7 (K7), keratin 19 (K19), oval cell (OV)‐6, epithelial cell adhesion molecule (EpCAM), and c‐Kit in both tumor and nontumor liver. We found that nontumor ductular reactions (DRs), specifically the proliferating cell nuclear antigen (PCNA) labeling index of the ductular reaction (PI‐DR), a surrogate for transit‐amplifying compartments, was an independent prognostic factor for both OS and DFS. By contrast, intratumoral expression of only one marker, absence of AFP, was associated with OS. PI‐DR was also independently associated with synchronous “multicentric occurrence” in hepatocellular carcinoma components, a feature of CHC that may predispose to metachronous multifocal tumorigenesis. Conclusion: Proliferative ductular reaction related to HPC activation is associated with recurrence of CHC. Background HPC activation is strongly associated with multifocal occurrence and related tumor recurrence, highlighting the critical role of background liver disease, a “field effect,” in the recurrence of CHC. (Hepatology 2012;56:1804–1816)

Risk factors and management for early and late intrahepatic recurrence of solitary hepatocellular carcinoma after curative resection

BACKGROUND Intrahepatic recurrence is a significant problem for patients who have undergone a hepatic resection for hepatocellular carcinoma (HCC). The objective of the present study was to identify risk factors and evaluate the management of early and late recurrence of solitary HCC after curative resection. METHODS Included in this study were 816 patients with solitary HCC who underwent a curative partial hepatectomy. Intrahepatic recurrence in these patients was followed up retrospectively. Prognosis and therapy for the recurrence were investigated and analysed. RESULTS Early and late intrahepatic recurrence occurred in 423 patients and 199 patients, respectively. Multivariate analysis showed that a tumour diameter >5 cm, the absence of a tumour capsule and the presence of microvascular invasion were correlated with early recurrence, whereas cirrhosis and alpha-fetal protein >400 μg/l were independent risk factors contributing to late recurrence. The 5-year survival of HCC patients with early recurrence was significantly lower than that of patients with late recurrence. Further curative treatment for intrahepatic recurrence offered a 5-year overall survival of 56.0%, which was better than alternative management. CONCLUSION Early and late recurrences of solitary HCC after curative resection are associated with different predictive factors. The time to recurrence and further curative treatment after recurrence were the best predictors of survival post recurrence.

Adjuvant transarterial chemoembolization after curative resection of hepatocellular carcinoma: a non-randomized comparative study.

BACKGROUND/AIMS Prevention of recurrence is the most important strategy to improve long-term survival after resection of hepatocellular carcinoma (HCC). This comparative study aimed to evaluate the outcome of adjuvant transarterial chemoembolization (TACE) after hepatectomy. METHODOLOGY From February 1996 and September 2001, 721 consecutive patients (adjuvant TACE treatment vs. control group; 145 vs. 576) with R0 resection for HCC were analyzed. The prospective data was analyzed retrospectively. RESULTS After a median follow-up of 75 months, 89 patients (61.4%) in the adjuvant TACE group and 355 patients (61.6%) in the control group had recurrent disease. There was no significant difference in the tumor recurrence rate between the 2 groups. There was significant difference in the tumor recurrence time between the 2 groups. The 1-, 3- and 5-year overall survival rates were 96.5%, 70.0% and 55.9%, respectively, for the adjuvant TACE group and 80.8%, 49.7% and 38.8%, respectively, for the control group. The 1-, 3- and 5-year disease-free survival rates were 79.9%, 54.9% and 48.4%, respectively, for the adjuvant TACE group and 60.2%, 39.8% and 31.5%, respectively, for the control group. The differences in the disease-free survival rates and the overall survival rates between the 2 groups were significant. In subgroup analysis, there was significant survival benefit in the adjuvant TACE group in the subgroup of patients with risk factors of recurrence - large tumor size, presence of satellite tumor nodules and narrow resection margin. CONCLUSIONS Adjuvant TACE improved surgical outcome in those patients with risk factors of HCC recurrence.

Retrospective analysis of transarterial chemoembolization and sorafenib in Chinese patients with unresectable and recurrent hepatocellular carcinoma

We explored the hypothesis that sorafenib may improve the effect of transarterial chemoembolization (TACE) in patients with recurrent hepatocellular carcinoma (HCC) and that longer sorafenib duration was associated with additional survival benefits. In this retrospective, nested case-controlled study, 1126 cases of unresectable HCC were collected. Patients with unresectable disease treated with TACE+sorafenib (n=245) and TACE alone (n=245) and those with recurrence after surgery treated with TACE+sorafenib (n=127) and TACE alone (n=127) were identified and matched according to sex, age, and lesion size and number. The clinicopathological factors associated with survival were examined by univariate and multivariate analyses. The mean duration of sorafenib treatment was 10.8±10.51 months. Sorafenib significantly increased the median survival time as compared to TACE alone (unresectable HCC: 20.23 vs. 13.97 months, respectively; p=0.013 and recurrent HCC: 30.7 and 18.22 months, respectively; p=0.003). The survival of patients with unresectable HCC was associated with the presence of portal vein tumor thrombus (HR=1.47, p=0.004) and treatment method (TACE+sorafenib combination therapy; HR=0.72, p=0.003). For patients with recurrent HCC, the presence of extrahepatic metastasis (HR=1.71, p=0.012) and treatment method (TACE+sorafenib therapy; HR=0.60, p=0.002) also was associated with survival. For patients treated with TACE+sorafenib, multivariate analysis showed decreased hazard of death with longer duration of sorafenib treatment (HR=0.9, p<0.001). Thus, sorafenib plus TACE may provide survival benefits, which may be related with sorafenib treatment duration, particularly for patients with HCC recurrence. Further clinical studies are required to confirm these results and identify which patients are most likely to benefit from this therapeutic strategy.

Changes in serum alpha fetoprotein in patients with recurrent hepatocellular carcinoma following hepatectomy

To study the change in serum alpha fetoprotein (AFP) of patients with recurrent hepatocellular carcinoma (HCC) after curative resection and to analyze its effect on the survival.

Axl Expression Stratifies Patients with Poor Prognosis after Hepatectomy for Hepatocellular Carcinoma.

Background Axl is a receptor tyrosine kinase which plays an important role in multiple human malignancies. Design The Axl expression was examined in several hepatocellular carcinoma(HCC) cell lines, paired tumor and nontumorous samples. Then, we examined cell growth curve, cell apoptosis and cell migration in SMMC-7721 cells over-expressed with Axl or siRNA against Axl, respectively. Finally, the prognostic value of Axl was investigated in a prospective cohort of 246 consecutive HCC patients undergoing curative hepatoectomy. Results We found Axl was positive in 22% of examined tumor tissues and all four cell lines. Over-expressing Axl in SMMC-7721 cells accelerated cell growth, cell migration and inhibited cell apoptosis, while knock-down of Axl exerted opposite effect. Axl expression was closely associated with serum AFP, multiple tumors, absence of encapsulation, microvascular invasion, and advanced BCLC or TNM stage. Patients with positive Axl staining had a higher 5-year recurrence rate (92% vs. 71%, P<0.001) and a lower 5-year survival rate (9% vs. 48%, P<0.001) than those with negative staining. The multivariate analyses showed that Axl expression was an independent factor for both tumor recurrence (HR: 1.725; 95% CI: 1.219–2.441) and survival (1.847; 1.291–2.642). Conclusion Axl expression suggests more aggressive tumor invasiveness and predicts worse prognosis for HCC patients undergoing resection.

Sorafenib down-regulates c-IAP expression post-transcriptionally in hepatic carcinoma cells to suppress apoptosis

Hepatocellular carcinoma (HCC) is one of leading causes of cancer-related death with a heterogeneous patient demographic and divergent pathogenic pathways. Sorafenib is the first effective drug approved for the treatment of HCC. Although it is known that sorafenib promotes apoptosis of HCC cells, the underlying mechanism remains largely obscure. Here we report that sorafenib down-regulates protein expression of the anti-apoptotic protein c-IAP1 in a time- and dose-dependent manner in HCC cells in vitro and in vivo. Furthermore, we demonstrate that sorafenib represses c-IAP1 levels without altering its transcription or protein stability. Instead, sorafenib attenuates c-IAP1 translation by targeting the internal ribosome entry site (IRES) within the c-IAP1 mRNA. Finally, ectopic expression of c-IAP1 alleviates sorafenib induced cancer cell apoptosis. In conclusion, our data highlight a previously unidentified pathway that contributes to sorafenib mediated HCC cell apoptosis and as such provide novel mechanistic insight into the rational use of sorafenib in treating HCC.

Adjuvant Transarterial Chemoembolization Following Liver Resection for Intrahepatic Cholangiocarcinoma Based on Survival Risk Stratification

BACKGROUND The effectiveness of adjuvant transarterial chemoembolization (TACE) for intrahepatic cholangiocarcinoma (ICC) after hepatectomy remains unclear. This study was performed to identify ICC patients who would benefit from adjuvant TACE. PATIENTS AND METHODS The study included 553 patients who underwent hepatectomy for ICC between January 2008 and February 2011 at the Eastern Hepatobiliary Surgery Hospital and who were treated with or without TACE (122 with TACE and 431 without TACE). Survival risk stratification was performed using the established prognostic nomogram (ICC nomogram). The predictive performance was evaluated by concordance index and calibration. The tumor recurrence and overall survival (OS) rates were analyzed by the Kaplan-Meier method before and after propensity score matching (PSM). RESULTS The predictive performance of the ICC nomogram was demonstrated by the well-fitted calibration curves and an optimal c-index of 0.71 for OS prediction. In the whole cohort, the 5-year recurrence and OS rates between the TACE and non-TACE groups were significantly different (5-year recurrence: 72.9% vs. 78.1%; OS: 38.4% vs. 29.7%). After 1:1 PSM, the TACE and non-TACE groups (122 patients each) had similar 5-year recurrence and OS rates (5-year recurrence: 72.9% vs. 74.2%; OS: 38.4% vs. 36.0%). By survival risk stratification based on ICC nomogram, only the patients in the lowest tertile (nomogram scores ≥77) benefited from adjuvant TACE (TACE vs. non-TACE groups: 90.4% vs. 95.9% for 5-year recurrence; 21.3% vs. 6.2% for 5-year OS). CONCLUSION Adjuvant TACE following liver resection might be suitable for ICC patients with high ICC nomogram scores (≥77). IMPLICATIONS FOR PRACTICE The accurate predictive performance of the established prognostic nomogram for intrahepatic cholangiocarcinoma (ICC) following liver resection was reconfirmed in an independent cohort with 553 patients. Based on the survival risk stratification using the nomogram, adjuvant transarterial chemoembolization following liver resection might be suitable only for ICC patients with high scores from the nomogram.